What if Alzheimer’s disease is caused, at least in part, by infections? An intriguing study in Science Translational Medicine, from researchers at Harvard University, led to provocative speculation in the New York Times and other major news outlets this summer. “I got asked more questions about this paper than probably anything in the last couple of years,” says Erik Roberson, M.D., Ph.D., co-director of the UAB Center for Neurodegeneration and Experimental Therapeutics in the UAB School of Medicine, associate professor of neurology and neurobiology, and Virginia B. Spencer Scholar in Neuroscience at UAB. “It has gotten a lot of people thinking and talking and asking questions.”

First, Roberson says, a little backstory is in order. In 1906, when Dr. Alois Alzheimer reported the first case of the disease that made him famous, he described a mass of “plaques” and “tangles” in the brain of an afflicted patient, known as Auguste D. But it wasn’t until the 1980s, Roberson explains, that researchers discovered that the main component of those plaques was a protein fragment called amyloid beta; the tangles were made up of a protein called tau.

“The idea that amyloid beta is the main cause of Alzheimer’s disease, what’s known as the ‘amyloid hypothesis,’ has been the main driver in the field” ever since, Roberson says. “There’s lots of evidence that it is part of the disease. That led to lots of trials of drugs to reduce amyloid beta production and inhibitors of aggregation of amyloid beta, but none of those have gone particularly well.”

A new narrative for Alzheimer’s

There are many reasons why that may be the case, Roberson says. For instance, the drugs might not have been able to infiltrate the blood-brain barrier. “But there has been a camp that argues that maybe amyloid beta isn’t the problem,” he says. “Maybe it’s a good thing; part of the brain’s attempt to respond to what is really happening in Alzheimer’s disease.”

Erik RobersonThe Science Translational Medicine paper explores a correlate of that idea — demonstrating that amyloid beta has antibacterial effects. “The main message of the paper is that amyloid beta coats yeast and fungi to prevent them from growing,” says Roberson. That finding “feeds a bigger narrative that has been cropping up over the past year,” he adds: “that infections are the cause of Alzheimer’s disease.”

These wouldn’t need to be life-threatening attacks. The theory, Roberson says, is that “maybe even a mild infection, the kind that many of us are exposed to, could do it. In the course of fighting off that infection, the brain makes amyloid beta to seal the microbes off in plaques, and that ends up having toxic effects.”

This is a “completely different potential cause of Alzheimer’s disease that has not been high on the radar,” Roberson says. In March, a group of about 30 researchers published an editorial in the Journal of Alzheimer’s Disease that summarized the available evidence that microbes could be an Alzheimer’s trigger. “There has been a lot of indirect evidence,” Roberson says. “For example, people with Alzheimer’s disease are more likely to have antibodies against the herpes virus. But that’s not the same thing as proving that herpes is the cause.” Still, the March editorial “got discussion going in the field,” says Roberson, “and I think that is why this subsequent Science Translational Medicine paper attracted so much attention.”

“An interesting idea worthy of more study”

It is a “good paper,” Roberson says. “No one paper generally nails down a question in science; it needs to be reproduced and tried in different species, with different types of amyloid beta and other infectious agents, but this is a good start.” And it helps point to the broader question of the ultimate cause of Alzheimer’s disease, Roberson adds.

About 1 percent of people have a genetic mutation that leads to Alzheimer’s, and there are genes that are risk factors in others, “but we don’t really know what is the cause,” Roberson says. The contention that amyloid beta is actually an “antimicrobial peptide is an interesting idea worthy of more study,” but it will be difficult to replicate the research in humans, Roberson points out. “It’s fairly easy to look at this question in animal models, but not in humans. We can only study someone’s brain after they have died, at a much later stage of the disease.”

Investigating a promising therapy

Meanwhile, Roberson’s lab is pursuing another longstanding Alzheimer’s question: What is the relationship between amyloid and tau, the protein responsible for the tangles in Alzheimer’s disease? “If you make a mouse without tau, amyloid beta doesn’t have its toxic effects,” Roberson says. “They require the presence of tau to have a full effect. In people, there are questions about that interaction as well. The amyloid beta accumulates in a different part of the brain than the tau accumulates. So maybe you need both of those hits, or maybe one is causing or enabling the other. We still don’t know.”

While they study that very question, Roberson’s team is also moving forward with tests of a compound that blocks the interaction between tau and another protein, fyn, that is important in these processes of Alzheimer’s. “If you get rid of one or the other, it’s a good thing,” Roberson says. “That is easy in mice, but difficult in patients.” Working with drug chemistry experts at Southern Research, Roberson’s lab has found several compounds that could block the tau-fyn linkup. They are now sifting these “hits” to find the most appropriate candidate compounds, Roberson says. “If we can prevent them from interacting, we believe it will have a beneficial effect.”

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